Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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ORAL CARE COMPOSITIONS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of priority from U.S. Provisional
Application No.
62/549,085, entitled: "Oral Care Compositions and Uses Thereof', the contents
of which are
hereby incorporated by reference herein, in their entirety.
BACKGROUND
[0002] Bacteria attached to an oral surface can cause local and systemic
pathology. For example,
periodontitis and caries are caused by oral surface bacterial biofilm
formation, and are among the
most common oral diseases worldwide. Seeding of oral cavity bacteria into the
bloodstream can
occur during dental procedures and result in serious infections such as
endocarditis and
prosthetic joint infection.
[0003] A need exists for oral care products having an improved anti-bacterial
effect to prevent
and/or decrease the incidence of local and systemic pathology arising from
bacterial attachment
to an oral surface. The compositions and methods of the present invention
address this need.
BRIEF SUMMARY
100041 In some embodiments, the present invention provides a composition
comprising an
amphiphilic macromolecule (AM). In some embodiments, the AMs of the present
invention are
effective in (1) preventing or decreasing oral surface bacterial attachment,
(2) stabilizing flavor
in an oral care composition, or (3) both preventing or decreasing oral surface
bacterial
attachment and stabilizing flavor in an oral care composition.
[0005] In some embodiments, the present invention provides an oral care
composition
comprising any one of the compounds described herein.
DETAILED DESCRIPTION
100061 Some embodiments of the present invention provide a composition
comprising a
compound having the structure of Formula (I):
1
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0 0 0
0 0 0
rOr
Formula (I)
wherein:
R is NH(CH2).PO4, wherein m is an integer from 1 to 6;
each n is independently selected from an integer between 2 and 20; and
y is an integer from 100 to 120; and
an orally acceptable carrier.
[0007] In some embodiments, the compound having a structure of Formula (1),
has the structure
of Compound A:
0
%
1,-
113
O. 0
0 c- )
Or 1:5\
Compound A
[0008] In some embodiments, the compound having a structure of Formula (I),
has the structure
of Compound B:
2
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,
0 __________________________________ C 0
0 -`0
HO
P N
113
OH 0 0
0
44¨ o
Compound B
[0009] Other embodiments provide a composition comprising a compound having a
structure of
Formula ( H ):
%
)..,}
0 ()
Formula (II)
wherein:
R is NH(CH2),I304, wherein m is an integer from 1 to 6;
each n is independently from an integer between 2 and 20; and
y is an integer from 100 to 120; and
an orally acceptable carrier.
[0010] In some embodiments, m is 1, 2, 3, 4, 5 or 6. In some embodiments, m is
2.
[0011] In some embodiments, each n is independently selected from an integer
between 3 and
19. In further embodiments, each n is independently selected from an integer
between 4 and 18.
In other embodiments, each n is independently selected from an integer between
4 and 15. In
some embodiments, each n is independently selected from an integer between 4
and 12. Other
embodiments provide a compound wherein each n is independently selected from
an integer
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between 4 and 10. In some embodiments, each n is 4. In some embodiments, each
n is 10. In
other embodiments, each n is independently 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17,
18, 19 or 20.
100121 In some embodiments, y is 100, 101, 102, 103, 104, 105, 106, 107, 108,
109, 110, 111,
112, 113, 114, 115, 116, 117, 118, 119 or 120. In some embodiments, y is an
integer from 105
to 118. In some embodiments, y is an integer from 108 to 117. In some
embodiments, y is an
integer from 110 to 115. In some embodiments, y is 113.
100131 Still further embodiments provide a composition comprising a compound
of Formula (II),
wherein the compound has the structure of Compound C:
0
0 ______________________________________ 0
0,
HO" \OH 1 0 / 113
0
()-
Compound C , and
an orally acceptable carrier.
100141 While other embodiments provide a composition comprising a compound of
Formula
(II), wherein the compound has the structure of Compound D:
P"
HO
OH 00
0
Compound I): and
an orally acceptable carrier.
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[0015] In some embodiments, the present invention provides a composition
comprising any one
of the compounds described herein. In some embodiments, the compositions are
oral care
compositions. In some embodiments, the oral care compositions comprise an
orally acceptable
carrier.
[0016] As used herein, the terms "oral composition(s)" or "oral care
composition(s)" refer to a
composition that is delivered to one or more surfaces of the oral cavity.
Generally, during the
normal course of use, the composition is not swallowed; rather, it is retained
in the oral cavity for
a time sufficient to contact one or more surfaces of the oral cavity and
provide the desired
benefit. Examples of such compositions include, but are not limited to,
toothpaste, mouthwash
or mouth rinse, oral gel, denture cleanser, and the like.
[0017] As used herein, the term "mouthrinse" or "mouthwash" refers to oral
care compositions
that are substantially liquid in character. In such a preparation the orally
acceptable carrier
typically has an aqueous phase comprising water or a water and alcohol
mixture. Further, in
various embodiments, the oral carrier includes a humectant and surfactant as
described below. In
various embodiments, the alcohol is typically ethyl alcohol.
[0018] In some embodiments, the oral care compositions may further include one
or more
fluoride ion sources, e.g., soluble fluoride salts. A wide variety of fluoride
ion-yielding materials
can be employed as sources of soluble fluoride in the present compositions.
Examples of suitable
fluoride ion-yielding materials are found in U.S. Pat. No. 3,535,421, to
Briner et al.; U.S. Pat.
No. 4,885,155, to Parran, Jr. et al. and U.S. Pat. No. 3,678,154, to Widder et
al., each of which
are incorporated herein by reference. Representative fluoride ion sources used
with the present
invention include, but are not limited to, stannous fluoride, sodium fluoride,
potassium fluoride,
sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate,
amine fluoride,
ammonium fluoride, and combinations thereof. In certain embodiments the
fluoride ion source
includes stannous fluoride, sodium fluoride, sodium monofluorophosphate as
well as mixtures
thereof. Where the formulation comprises calcium salts, the fluoride salts are
preferably salts
wherein the fluoride is covalently bound to another atom, e.g., as in sodium
monofluorophosphate, rather than merely ionically bound, e.g., as in sodium
fluoride.
[0019] In other embodiments, the compositions of the present invention may
contain anionic
surfactants, for example, water-soluble salts of higher fatty acid
monoglyceiide monosulfates,
such as the sodium salt of the monosulfated monoglyceride of hydrogenated
coconut oil fatty
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acids such as sodium N- methyl N-cocoyl taurate, sodium coco-glyceride
sulfate; higher alkyl
sulfates, such as sodium lauryl sulfate; higher alkyl-ether sulfates, e.g., of
formula
CH3(CH2).CH2(OCH2CH2),,OS03X, wherein m is 6-16, e.g., 10, n is 1-6, e.g., 2,
3 or 4, and X is
Na or , for example sodium laureth-2 sulfate (CH3(CH2)10CH2(OCH2CH2)20S03Na);
higher
alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate (sodium lauryl
benzene
sulfonate); higher alkyl sulfoacetates, such as sodium lauryl sulfoacetate
(dodecyl sodium
sulfoacetate), higher fatty acid esters of 1,2 dihydroxy propane sulfonate,
sulfocolaurate (N-2-
ethyl laurate potassium sulfoacetamide) and sodium lauryl sarcosinate. By
"higher alkyl" is
meant, e.g., C6-3o alkyl. In particular embodiments, the anionic surfactant
(where present) is
selected from sodium lauryl sulfate and sodium ether lauryl sulfate. When
present, the anionic
surfactant is present in an amount which is effective, e.g., > 0.001% by
weight of the
formulation, but not at a concentration which would be irritating to the oral
tissue, e.g., 1 %, and
optimal concentrations depend on the particular formulation and the particular
surfactant. In one
embodiment, the anionic surfactant is present at from 0.03% to 5% by weight,
e.g., 1.5%.
[0020] Cationic surfactants may also be included in compositions of the
present invention, and
can be broadly defined as derivatives of aliphatic quaternary ammonium
compounds having one
long alkyl chain containing 8 to 18 carbon atoms such as lauryl
trimethylammonium chloride,
cetyl pyridinium chloride, cetyl trimethylammonium bromide,
di-
isobutylphenoxyethyldimethylbenzylammonium chloride, coconut
alkyltrimethylammonium
nitrite, cetyl pyridinium fluoride, and mixtures thereof. Illustrative
cationic surfactants are the
quaternary ammonium fluorides described in U.S. Pat. No. 3,535,421, to Briner
et al., herein
incorporated by reference. Certain cationic surfactants can also act as
germicides in the
compositions.
[0021] Illustrative nonionic surfactants that can be used in some embodiments
of the present
invention can be broadly defined as compounds produced by the condensation of
alkylene oxide
groups (hydrophilic in nature) with an organic hydrophobic compound which may
be aliphatic or
alkylaromatic in nature. Examples of suitable nonionic surfactants include,
but are not limited to,
the Pluronics, polyethylene oxide condensates of alkyl phenols, products
derived from the
condensation of ethylene oxide with the reaction product of propylene oxide
and ethylene
diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary
amine oxides, long
chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of
such materials. In
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a particular embodiment, the composition of the invention comprises a nonionic
surfactant
selected from polaxamers (e.g., polaxamer 407), polysorbates (e.g.,
polysorbate 20), polyoxyl
hydrogenated castor oils (e.g., polyoxyl 40 hydrogenated castor oil), and
mixtures thereof.
[0022] Illustrative amphoteric surfactants that can be used in the
compositions of the invention
include betaines (such as cocamidopropyl betaine), derivatives of aliphatic
secondary and tertiary
amines in which the aliphatic radical can be a straight or branched chain and
wherein one of the
aliphatic substituents contains about 8-18 carbon atoms and one contains an
anionic water-
solubilizing group (such as carboxylate, sulfonate, sulfate, phosphate or
phosphonate), and
mixtures of such materials.
[0023] Illustrative zwitterionic surfactants that can be used in some
embodiments of the present
invention include derivatives of aliphatic quaternary ammonium, phosphonium
and sulfonium
compounds in which the aliphatic radical can be a straight or branched chain
and wherein one of
the aliphatic substituents contains about 8-18 carbon atoms and one contains
an anionic water-
solubilizing group (such as carboxy, sulfonate, sulfate, phosphate or
phosphonate). The
surfactant or mixtures of compatible surfactants can be present in the
compositions of the present
invention in 0.1% to 5%, in another embodiment 0.3% to 3% and in another
embodiment 0.5%
to 2% by weight of the total composition.
[0024] The oral care compositions of the invention may also include a
flavoring agent. Flavoring
agents which are used in the practice of the present invention include, but
are not limited to,
essential oils and various flavoring aldehydes, esters, alcohols, and similar
materials, as well as
sweeteners such as sodium saccharin. Examples of the essential oils include
oils of spearmint,
peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram,
cinnamon, lemon, lime,
grapefruit, and orange. Also useful are such chemicals as menthol, carvone,
and anethole.
Certain embodiments employ the oils of peppermint and spearmint. In some
embodiments, the
flavoring agent is incorporated in the oral composition at a concentration of
0.01 to 1% by
weight.
[0025] In some embodiments, compounds of Formulas (I) and (II) help to
solubilize the
flavoring agent in the oral care composition.
[0026] The oral care compositions of the invention also may include one or
more chelating
agents able to complex calcium found in the cell walls of the bacteria.
Binding of this calcium
weakens the bacterial cell wall and augments bacterial lysis.
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10027) Another group of agents suitable for use as chelating or anti-calculus
agents in the present
invention are the soluble pyrophosphates. The pyrophosphate salts used in the
present
compositions can be any of the alkali metal pyrophosphate salts. In certain
embodiments, salts
include tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate,
trialkali metal
monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are
sodium or
potassium. The salts are useful in both their hydrated and unhydrated forms.
An effective amount
of pyrophosphate salt useful in the present composition is generally enough to
provide least 0.1
wt. 4310 pyrophosphate ions, e.g., 0.1 to 3 wt 5, e.g., 0.1 to 2 wt %, e.g.,
0.1 to 1 wt%, e.g., 0.2 to
0.5 wt%. The pyrophosphates also contribute to preservation of the
compositions by lowering
the effect of water activity.
[0028] The oral care compositions of the invention also optionally include one
or more
polymers, such as polyethylene glycols, polyvinyl methyl ether maleic acid
copolymers,
polysaccharides (e.g., cellulose derivatives, for example carboxymethyl
cellulose, or
polysaccharide gums, for example xanthan gum or carrageenan gum). Acidic
polymers, for
example polyacrylate gels, may be provided in the form of their free acids or
partially or fully
neutralized water soluble alkali metal (e.g., potassium and sodium) or
ammonium salts. Certain
embodiments include 1 :4 to 4: 1 copolymers of maleic anhydride or acid with
another
polymerizable ethylenically unsaturated monomer, for example, methyl vinyl
ether
(methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about
1,000,000. These
copolymers are available for example as Gantrez AN 139(M.W. 500,000), AN 1 19
(M.W.
250,000) and S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals
Corporation.
[0029] Other operative polymers include those such as the 1:1 copolymers of
maleic anhydride
with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or
ethylene, the latter
being available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA
Grade 61,
and 1 : 1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate,
methyl or ethyl
acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
[0030] Suitable generally, are polymerized olefinically or ethylenically
unsaturated carboxylic
acids containing an activated carbon-to-carbon olefinic double bond and at
least one carboxyl
group, that is, an acid containing an olefinic double bond which readily
functions in
polymerization because of its presence in the monomer molecule either in the
alpha-beta position
with respect to a carboxyl group or as part of a terminal methylene grouping.
Illustrative of such
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acids are acrylic, methactylic, ethacrylic, alpha-chloroacrylic, crotonic,
beta-acryloxy propionic,
sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itaconic,
citraconic,
mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, 2-
cyclohexylacrylic,
angelic, umbellic, fiimaric, maleic acids and anhydrides. Other different
olefinic monomers
copolymerizable with such carboxylic monomers include vinylacetate, vinyl
chloride, dimethyl
maleate and the like. Copolymers contain sufficient carboxylic salt groups for
water-solubility.
100311 A further class of polymeric agents includes a composition containing
homopolymers of
substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and
salts thereof, in
particular where polymers are based on unsaturated sulfonic acids selected
from
acrylamidoalykane sulfonic acids such as 2-acrylamide 2 methylpropane sulfonic
acid having a
molecular weight of about 1,000 to about 2,000,000, described in U.S. Pat. No.
4,842,847, Jun.
27, 1.989 to Zahid, incorporated herein by reference.
100321 Another useful class of polymeric agents includes polyamino acids,
particularly those
containing proportions of anionic surface-active amino acids such as aspartic
acid, glutamic acid
and phosphoserine, as disclosed in U.S. Pat. No. 4,866,161 Sikes et al.,
incorporated herein by
reference.
100331 In preparing oral care compositions, it is sometimes necessary to add
some thickening
material to provide a desirable consistency or to stabilize or enhance the
performance of the
formulation. In certain embodiments, the thickening agents are carboxyvinyl
polymers,
carrageenan, xanthan gum, hydroxyethyl cellulose and water soluble salts of
cellulose ethers
such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl
cellulose.
Natural gums such as karaya, gum arabic, and gum tragacanth can also be
incorporated.
Colloidal magnesium aluminum silicate or finely divided silica can be used as
component of the
thickening composition to further improve the composition's texture. In
certain embodiments,
thickening agents in an amount of about 0.5% to about 5.0% by weight of the
total composition
are used.
100341 The pH of the compositions of the present invention is generally
between about 4.5 and
about 10. The pH can be controlled with acid (e.g., citric acid or benzoic
acid) or base (e.g.,
sodium hydroxide) or buffered (with sodium citrate, benzoate, carbonate, or
bicarbonate,
di sodium hydrogen phosphate, or sodium dihydrogen phosphate, for example).
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[0035] Colorants among those useful herein include pigments, dyes, lakes and
agents imparting a
particular luster or reflectivity such as pearling agents. In various
embodiments, colorants are
operable to provide a white or light-colored coating on a dental surface, to
act as an indicator of
locations on a dental surface that have been effectively contacted by the
composition, and/or to
modify appearance, in particular color and/or opacity, of the composition to
enhance
attractiveness to the consumer. Any orally acceptable colorant can be used,
including FD&C
dyes and pigments, talc, mica, magnesium carbonate, calcium carbonate,
magnesium silicate,
magnesium aluminum silicate, silica, titanium dioxide, zinc oxide, red,
yellow, brown and black
iron oxides, ferric ammonium ferrocyanide, manganese violet, ultramarine,
titaniated mica,
bismuth oxychloride, and mixtures thereof. One or more colorants are
optionally present in a
total amount of 0.001 wt.% to 10 wt.%, for example 0.01 wt.% to 5 wt.% or 0.1
wt.% to 1 wt.%.
[0036] In some embodiments, the compositions of the present invention comprise
a tartar control
(anticalculus) agent. Tartar control agents among those useful herein include
salts of any of these
agents, for example their alkali metal and ammonium salts: phosphates and
polyphosphates (for
example pyrophosphates), polyaminopropanesulfonic acid (AMPS), polyolefin
sulfonates,
polyolefin phosphates, diphosphonates such as azacycloalkane-2,2-
diphosphonates (e.g.,
azacycloheptane-2,2-diphosphonic acid), N-methyl azacyclopentane-2,3-
diphosphonic acid,
ethane-l-hydroxy-1,1-diphosphonic acid (EHDP) and ethane-1-amino-1,1-di
phosphonate,
phosphonoalkane carboxylic acids and. Useful inorganic phosphate and
polyphosphate salts
include monobasic, dibasic and tribasic sodium phosphates, sodium
tripolyphosphate,
tetrapolyphosphate, mono-, di-, tri- and tetrasodium pyrophosphates, sodium
trimetaphosphate,
sodium hexametaphosphate and mixtures thereof.
[0037] In further embodiments, the oral compositions of the present invention
comprise a saliva
stimulating agent useful, for example, in amelioration of dry mouth. Any
orally acceptable saliva
stimulating agent can be used, including without limitation food acids such as
citric, lactic,
malic, succinic, ascorbic, adipic, fumaric and tartaric acids, and mixtures
thereof. One or more
saliva stimulating agents are optionally present in saliva stimulating
effective total amount.
[0038] In yet other embodiments, the oral compositions of the present
invention comprise a
nutrient. Suitable nutrients include vitamins, minerals, amino acids, and
mixtures thereof.
Vitamins include Vitamins C and D, thiamine, riboflavin, calcium pantothenate,
niacin, folic
acid, nicotinamide, pyridoxine, cyanocobalamin, para-aminobenzoic acid,
bioflavonoids, and
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mixtures thereof. Nutritional supplements include amino acids (such as L-
tiyptophane, L-lysine,
methionine, threonine, levocarnitine and L-camitine), lipotropics (such as
choline, inositol,
betaine, and linoleic acid), and mixtures thereof.
[0039] In some embodiments, the present invention provides a method of
treating conditions
associated with the presence of oral bacteria comprising providing an oral
composition in
accordance with any of the above-described embodiments, and applying the oral
composition to
the oral cavity of the mammalian subject. In some embodiments, the method
comprises repeating
the application of the composition multiple times until the desired anti-
bacterial and/or anti-
inflammatory effects are achieved in the subject.
[0040] Further embodiments provide the use a composition as described herein
for inhibiting or
preventing bacterial adhesion to an oral cavity surface of a mammal. While
other embodiments
provide the use of a composition as described herein for treating, preventing
or inhibiting the
incidence of, or ameliorating the symptoms associated with, a systemic
infection in a mammal.
[0041] In some embodiments, the present invention provides a composition
comprising any one
of the compounds described herein. In other embodiments, the present invention
provides a
composition comprising a compound described in U.S. Patent No. 7,470,802. In
some
embodiments, the compounds described herein (e.g. Compounds A to D) can be
prepared in
accordance with the methods described in US 2011/0229416.
[0042] Further embodiments of the present invention provide an oral care
composition
comprising a compound of Formula (III):
A-X-Y-Z-R1 (III)
wherein: A is a carboxy group or is absent; X is a straight chain or branched
chain aliphatic
group containing 2 carbons to about 20 carbons wherein the aliphatic group is
substituted with 2
to about 20 hydroxy groups; Y is ¨C(3)--, ¨C(=S)--, or is absent; Z is 0, S or
NH; and R1
is a polyether, wherein one or more hydroxy groups of X are acylated with a
fatty acid residue;
and an orally acceptable carrier.
[0043] As used herein, the term polyether includes poly(alkylene oxides)
having between about
2 and about 150 repeating units. Typically, the poly(allcylene oxides) have
between about 50 and
about 110 repeating units. The alkylene oxide units contain from 2 to 10
carbon atoms and may
be straight chained or branched. Preferably, the alkylene oxide units contain
from 2 to 10 carbon
atoms. Poly(ethylene glycol) (PEG) is preferred. Alkoxy-, amino-, carboxy-,
and sulfo-
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terminated poly(alkylene oxides) are preferred, with methoxy-terminated
poly(alkylene oxides)
being more preferred.
[0044] A preferred polyether has the following structure:
R5¨(R6-0¨)a¨R6-Q-
wherein
R5 is a 1 to 20 carbon straight-chain or branched alkyl group, ¨OH, ¨0R7,
¨NH2, ¨
NHR7, ¨NHR7R43, ¨CO2H, ¨S03H (sulfo), ¨CH2-0H, ¨CH2-0117, ¨CH2-0¨CH2¨
R7, --CH2¨NH2, ¨CH2¨NHR7, ¨CH2¨NR7R8, ¨CH2C 02H, ¨CH2S03H, or ¨0¨
R6 is a 1 to 10 carbon straight-chain or branched divalent allcylene group;
each R7 and Rs is independently a 1 to 6 carbon straight-chain or branched
alkylene
group;
Q is ¨0¨, ¨S¨, or ¨NR7; and
a is an integer from 2 to 150, inclusive.
[0045] Another preferred polyether is methoxy terminated polyethylene glycol.
[0046] In a compound of Formula (III), a poly(alkylene oxide) can be linked to
the polyol, for
example, through an ether, thioether, amine, ester, thioester, thioamide, or
amide linkage.
Preferably, a poly(alkylene oxide) is linked to the polyol by an ester or
amide linkage in a
compound of Formula (III).
[0047] As used herein, the term fatty acid includes fatty acids and fatty oils
as conventionally
defined, for example, long-chain aliphatic acids that are found in natural
fats and oils. Fatty acids
typically comprise from about 2 to about 24 carbon atoms. Preferably, fatty
acids comprise from
about 6 to about 18 carbon atoms. The term "fatty acid" encompasses compounds
possessing a
straight or branched aliphatic chain and an acid group, such as a carboxylate,
sulfonate,
phosphate, phosphonate, and the like. The "fatty acid" compounds are capable
of "esterifying" or
forming a similar chemical linkage with hydroxy groups on the polyol. Examples
of suitable
fatty acids include caprylic, capric, lauric, myristic, myristoleic, palmitic,
palmitoleic, stearic,
oleic, linoleic, eleostearic, arachidic, behenic, erucic, and like acids.
Fatty acids can be derived
from suitable naturally occurring or synthetic fatty acids or oils, can be
saturated or unsaturated,
and can optionally include positional or geometric isomers. Many fatty acids
or oils are
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commercially available or can be readily prepared or isolated using procedures
known to those
skilled in the art.
[0048] Exemplary embodiments of the present disclosure will be illustrated by
reference to the
following examples, which are included to exemplify, but not to limit the
scope of the present
invention.
EXAMPLES
Example 1
[0049] Compound A was prepared as follows. CDI (82.0 mg, 0.51 mmol) was added
to a
solution containing Compound E (1.50 g, 0.25 mmol) in anhydrous DMF (10.5 mL).
a
1,... -=..,. .
0 0-1._
1
113
i
S Compound E
[0050] The reaction mixture was stirred for 1.5 h at room temperature under a
N2 atmosphere
and added to a solution of 2-aminoethyl dihydrogen phosphate (47.5 mg, 0.34
mmol) in water
(10.5 mL) containing Et3N (35 aL), and the mixture was stirred at room
temperature for 20 h.
The reaction mixture was concentrated in vacuo. The resulting solids were
dissolved in DCM
and washed once with 0.1 M HCl (aq). The organic layer was washed once with
saturated NaCI
(aq) solution and dried over anhydrous MgSO4. The solids were removed by
filtration and the
solvent was removed from the filtrate in vacuo. The resulting crude oil was
dissolved in DCM
and precipitated into cold Et20. Compound A was isolated via centrifugation at
3500 rpm for 5
min and decanting the supernatant. The pellet was washed with Et20 (50 mL x 3)
and isolated
via centrifugation.
[0051] A similar method was used to prepare Compound B, using Compound F as
the starting
material.
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0
0 0 0
/113
0 0 0
Compound F
100521 Specifically, Compound F was activated with CDI followed by treatment
with 2-
aminoethylphosphate to afford Compound B. Compounds C and D can be prepared
using
similar methods, using Compounds G and H, respectively, as the starting
materials.
o
04113
0
Compound G
o
I TO 041 13
0
Compound H
100531 Compounds G and H can be prepared in accordance with the methods
described in Tian,
L., Novel Amphiphilic Macromolecules for Drug Delivery Applications: Design,
Synthesis and
characterization. Rutgers University: 2004.
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[0054] Compounds E and F can be prepared in accordance with the methods
described in Tian et
al., Amphiphilic Scorpion-like Macromolecules: Design, Synthesis, and
Characterization.
Macromolecules 2004, 37(2), 538-543.
Example 2: Anti-Attachment Assay
[0055] Day 1: Over-Night Preparation: Fresh microbial cultures of Actinomyces
viscosus
(ATCC#43146) & Streptococcus oralis (ATCC#35037) were grown.
[0056] Day 2: Treatment:
[0057] An HAP coated MBEC Lid (Innovotech Catalog #19132) was placed into its
corresponding 96-well plate containing simple solutions or formulations
containing the
amphiphilic macromolecules for 60 minutes at 37 C. After this time, the plate
was rinsed to
remove excess or loosely bound material by dipping the MBEC lid in 1/4
concentrated TSB 10
times. The 1/4 TSB was then changed and the rinsing procedure repeated for a
total of three
rinsing cycles. Equal volume over-night cultures of A. viscosus & S. oralis
were mixed together
and the O.D. of the cultures was adjusted to 1.00 at 610 nm. To each of the 96
wells and 180 I
of bacteria solution was added, and the plate was incubated 3-4 hours at 37
C. Attached bacteria
were removed by placing the MBEC lid into fresh 1/4 TSB and sonicating for 2 x
2 minutes,
rotating the plate 180 between sonication rounds. A representative sample of
100 L was
removed from each well and transferred to a black, clear-bottom plate (Corning
Ref# 3904).
Bacteria count is measured by ATP bioluminescence using BacTiter-Glo Microbial
Cell
Viability Assay (Promega Ref# G8231) as per the manufacturer's instructions.
[0058] Table 1 (below) describes the results of the above-described
experiment.
Table 1
Compound % Reduction
A 65.0
46.2
42.3
40.2
47.4
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25.1
100591 Generally, a correlation between % reduction of bacterial adhesion and
how much
material was retained after rinsing on HAP-coated surfaces was observed. This
data is described
in Table 2 (below).
Table 2
Compound % Retained* % Retained** % Reduction of Bacterial
Adhesion
A 74 100 51.0
0 14 26.2
0 69 17.6
0 0 14.3
0 60 75.9
0 0 77.9
* HAP-coated QCM-D chips
** HAP-coated QCM-D chips (w/ Phosphate buffer)
Example 3: Flavor stabilization assay
100601 Peppermint flavor oil was dissolved in propylene glycol, a typical
procedure in the
production of commercial mouthwash formulations. Exemplary compositions of the
present
invention comprising compounds described herein at concentrations of 1 w/w%
and 2 w/w %; 7
w/w% propylene glycol; and 0.12 w/w% peppermint flavor are evaluated for
turbidity in order to
determine which compound(s) exhibited the greatest ability to solubilize
flavor. Table 3 (below)
describes the results of these evaluations.
Table 3
Compound Concentration (w/w %) Transmittance (normalized)
Water N/A 1
l'oloxomer 407 1 0.99
1 0
2 0
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1 0.019
0
1 0.37
2 0.78
A 1 0.19
0.90
Example 4
[0061] Compound A and Compound E are complexed with flavor and their ability
to provide
anti-attachment benefits, with and without flavor, is evaluated. Table 4
(below) describes the
results of these evaluations, which demonstrate that the presence of a
hydrophobic ingredient
(e.g. a flavor) does not meaningfully compromise the anti-attachment efficacy
of exemplary
compounds of the present invention.
Table 4
Compound % Reduction
A 51.0
A .4- Flavor 48.5
75.9
E 4- Flavor 78.8
Example 5
[0062] Hydroxyapatite discs (12 mm) are soaked in clarified saliva at 37 C
for 1 hour. After
this time, the discs are rinsed and treated with 1.5 mL of a 1 wt% solution
containing the
materials for 1 hour. The discs are rinsed 3 times and then set in 1.5 mL
bacteria solution (50/50
A. viscosus / S. oralis, with an O.D. = 2 @ 610 nm) for 3 hours. Discs are
rinsed, and then
stained with SYTO 9 dye (3.34 mM, Invitrogen LIVE/DEAD BacLIGHT (TM) Bacterial
Viability Kit (L7012), with a concentration of 6 uL/mL. Discs are then rinsed
twice with quarter
strength TSB buffer for final imaging.
Example 6
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10063) Table 5 (below) describes the formula of an exemplary oral care
composition of the
present invention.
Ingredient Wt. %
Amphiphilic Macromolecule 0-2
(e.g. Compounds A-H)
Antibacterial 0.01 - 0.1
Sodium saccharin 0.005 - 0.2
Sodium benzoate 0.01 -0.1
Potassium sorbate 0.01 - 1
Glycerin 0 - 15
Sorbitol 0- 15
Poloxainer 407 0 -2
Propylene Glycol 0 - 7
Flavor 0.05 - 1
Color 0.0001-0.005
Water Q. S.
[0064] Compositions of the present invention, including the exemplary
composition described in
Table 5 (above), can be prepared according to methods generally known to those
skilled in the
art.
[0065] As used throughout, ranges are used as shorthand for describing each
and every value
that is within the range. Any value within the range can be selected as the
terminus of the range.
[0066] All references cited herein are hereby incorporated by reference in
their entireties. In the
event of a conflict in a definition in the present disclosure and that of a
reference cited herein, the
present disclosure shall control.
[0067] Unless otherwise specified, all percentages and amounts expressed
herein and elsewhere
in the specification should be understood to refer to percentages by weight.
The amounts given
are based on the active weight of the material.
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(00681 While the present invention has been described with reference to
embodiments, it will be
understood by those skilled in the art that various modifications and
variations may be made
therein without departing from the scope of the present invention as defined
by the appended
claims.
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